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Semin Liver Dis 2013; 33(02): 147-156
DOI: 10.1055/s-0033-1345721
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Molecular Mechanisms of HBV-Associated Hepatocarcinogenesis

Francesca Guerrieri
1   Department of Internal Medicine (DMISM) and Sapienza Life Nanoscience Laboratory (SLN-Lab), Sapienza University, Rome, Italy
2   LEA INSERM U785 - DMISM, Sapienza University, Rome, Italy
,
Laura Belloni
1   Department of Internal Medicine (DMISM) and Sapienza Life Nanoscience Laboratory (SLN-Lab), Sapienza University, Rome, Italy
3   IIT Centre for Life Nanoscience (CLNS), Rome, Italy
,
Natalia Pediconi
3   IIT Centre for Life Nanoscience (CLNS), Rome, Italy
4   Department of Molecular Medicine, Sapienza University, Rome, Italy
,
Massimo Levrero
1   Department of Internal Medicine (DMISM) and Sapienza Life Nanoscience Laboratory (SLN-Lab), Sapienza University, Rome, Italy
2   LEA INSERM U785 - DMISM, Sapienza University, Rome, Italy
3   IIT Centre for Life Nanoscience (CLNS), Rome, Italy
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Publikationsdatum:
08. Juni 2013 (online)

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Abstract

Hepatitis B virus (HBV) contributes to hepatocellular carcinoma (HCC) development through direct and indirect mechanisms. HBV-DNA integration into the host genome occurs at early steps of clonal tumor expansion and induces both genomic instability and direct insertional mutagenesis of diverse cancer-related genes. Prolonged expression of the viral regulatory protein HBx and the large envelope protein deregulate the cellular transcription program and proliferation control and sensitize liver cells to carcinogenic factors. Epigenetic changes targeting the expression of tumor suppressor genes occur early in the development of HCC. A major role is played by HBx that is recruited on cellular chromatin and modulates chromatin dynamics at specific gene loci. Compared with tumors associated with other risk factors, HBV-related tumors have a higher rate of chromosomal alterations and p53 inactivation by mutations, overexpress fetal liver/hepatic progenitor cells genes, and show a specific activation of the AKT pathway. The wnt/β-catenin pathway is also often activated, but HBV-related tumors display a low rate of activating β-catenin mutations. All available evidence strongly supports the notion that chronic HBV infection triggers both common and etiology-specific oncogenic pathways, thus playing a direct role beyond stimulation of host immune responses and chronic necroinflammatory liver disease.

Keywords

hepatocellular carcinoma (HCC) - hepatitis B virus (HBV) - HBx protein - epigenetics - miRNAs
 

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